A Case of Sporadic Blau Syndrome with an Uncommon Clinical Course.

BACKGROUND: Sporadic Blau syndrome (SBS), a rare systemic inflammatory disease in children, is associated with NOD2 gene mutations. SBS is often misdiagnosed as juvenile idiopathic arthritis (JIA) because of their similar clinical manifestations. Herein, we present a case of SBS with an uncommon clinical course. CASE PRESENTATION: An 11-year-old girl with recurrent right ankle swelling for 4 years was referred to our hospital. One month before admission, she developed an intermittent high fever. She was diagnosed with systemic-onset JIA on the basis of physical and blood examination results. She was treated with ibuprofen, prednisolone, and methotrexate for 5 years. During this period, her joint lesion showed neither bone destruction nor joint space narrowing on radiography, which are characteristics of JIA. Twelve months after the termination of methotrexate treatment, she presented with bilateral panuveitis. A missense mutation, p.(R587C), was detected in her NOD2 gene, and she was diagnosed with SBS. Then, infliximab treatment was started, and her visual acuity recovered. CONCLUSION: SBS may sometimes be misdiagnosed as JIA. A joint lesion without bone destruction might be a key feature to distinguish SBS from JIA. Analysis of the NOD2 gene is recommended in such cases.

Autoimmune neutropenia of infancy with multiple brain abscesses during the course of human herpesvirus-6 infection.

Autoimmune neutropenia of infancy is characterized by recurrent infections such as pneumonia, otitis media, impetigo, purulent skin regions, gastritis, and upper respiratory infection. However, severe bacterial infection is uncommon. This report documents a 9-month-old boy presenting with autoimmune neutropenia in association with multiple brain abscesses during the course of human herpesvirus (HHV)-6 infection. HHV-6 has a tendency of neurovirulence, which can destroy the blood-brain barrier and facilitate the easy invasion of agents inside the brain. Although autoimmune neutropenia of infancy is benign and self limiting, it must be emphasized that severe bacterial infection will be induced by concurrent viral infection in this specific disorder.

Expression of CD180, a toll-like receptor homologue, is up-regulated in children with Kawasaki disease.

Kawasaki disease (KD) is an acute febrile illness in childhood characterized by the formation of aneurysms in coronary arteries. It is believed that KD is caused by infectious agents because of its epidemic waves and high incidence of familial occurrence. Because an increase in the levels and dysfunction of B cells in peripheral blood was reported in KD, we investigated the expression of cluster of differentiation 180 (CD180), a toll-like receptor homologue, in the B cells of children with KD, and in those with bacterial or viral infections. The percentages of CD180 positive B cells were significantly higher in children with KD or viral infections than in those with bacterial infections or in healthy controls. When the expression levels of CD180 were compared by using the mean fluorescent intensity ratio of patients to healthy controls, the level of CD180 expression was also significantly up-regulated in children with KD or viral infections. To clarify the effect of viral infection on the expression of CD180, B cells were stimulated with poly inosinic-cytidyric acid [poly(IC)], a synthetic double-stranded RNA. Poly(IC) clearly enhanced CD180 expression in B cells in vitro, both at the protein and messenger RNA levels. These results suggest that similar mechanisms may be involved in the up-regulation of B cell CD180 expression in patients with either KD or viral infections.

Partial tandem duplication of MLL gene in acute myeloid leukemia with translocation (11;17)(q23;q12-21).

Translocation 11q23 and MLL gene rearrangements are commonly observed in acute myeloid leukemia (AML) in association with the myelomonocytic or monocytic feature. We describe a case involving a 15-year-old patient with AML characterized by leukemic cells exhibiting translocation (11;17)(q23;q12-21) and MLL gene rearrangement. No fusion partner gene of the MLL gene was identified, including RARalpha(17q12) or AF17 (17q21); however, a partial tandem duplication of the MLL exon 11/exon 10 was detected in leukemic cells via a 3'RACE method for detection of unknown partner genes. The patient has been in remission for more than 2 years without hematopoietic stem cell transplantation.

Successful bone marrow transplantation in a patient with c-mpl-mutated congenital amegakaryocytic thrombocytopenia from a carrier donor.

Congenital amegakaryocytic thrombocytopenia (CAMT) is characterized by severe thrombocytopenia and the absence of megakaryocytes in bone marrow. Furthermore, mutation of the c-mpl gene has been identified as a cause of this disorder. The only curative treatment is allogeneic stem cell transplantation (SCT). The current report describes a patient exhibiting c-mpl mutation in both alleles who underwent transplantation of allogeneic bone marrow donated by her brother, a c-mpl mutated carrier, employing a fludarabine-based conditioning regimen. Engraftment and reconstitution of hematopoietic cells was rapid and without complications. These findings suggest that the carrier donor displaying the c-mpl mutation can serve as a donor source for SCT.

Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions.

Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset.

Regulatory mechanisms of Th2 cytokine-induced eotaxin-3 production in bronchial epithelial cells: possible role of interleukin 4 receptor and nuclear factor-kappaB.

BACKGROUND: Several cytokine combinations have been shown to induce eotaxins in bronchial epithelium. The mechanism for differential regulation of eotaxin expression remains unclear. OBJECTIVE: To investigate the regulatory mechanisms of eotaxin-3 production vs eotaxin-1 production in cultured bronchial epithelium. METHODS: Messenger RNA (mRNA) expression levels of eotaxin-1, eotaxin-2, and eotaxin-3 in a human bronchial epithelial cell line (BEAS-2B) and a normal human bronchial epithelial cell were examined using reverse transcriptase-polymerase chain reaction. Protein production was determined by enzyme-linked immunosorbent assay. Receptor expression was examined by flow cytometry. Phosphorylation of signal transducer and activator of transcription factor 6 (STAT6) was examined by immunoblotting. RESULTS: Eotaxin-1 and eotaxin-3, but not eotaxin-2, mRNA expressions were induced by stimulation with interleukin (IL) 13 or IL-4. However, eotaxin-3 was the only protein detected after stimulation. A consistent 10-fold difference in the potency of IL-13- and IL-4-mediated induction of eotaxin-3 mRNA expression was observed. Interleukin 4 induced more potent induction of STAT6 phosphorylation compared with IL-13. The BEAS-2B cells were observed to express types 1 and 2 IL-4 receptors. Pretreatment with tumor necrosis factor a enhanced IL-4-induced eotaxin-1, but not eotaxin-3, mRNA expression. An inhibitor of nuclear factor-KB inhibited IL-13- and IL-4-induced eotaxin-1 gene expressions. However, it enhanced eotaxin-3 gene expression. CONCLUSIONS: These results suggest that differences in the potency of IL-13- and IL-4-mediated induction of eotaxin-3 might be explained by expression of types 1 and 2 IL-4 receptors in bronchial epithelium. Differences in eotaxin-1 and eotaxin-3 mRNA and protein expression might be due to differential effects of nuclear factor-kappaB on gene expression.

A polymorphism in the promoter of the CD14 gene (CD14/-159) is associated with the development of coronary artery lesions in patients with Kawasaki disease.

OBJECTIVE: To investigate whether a polymorphism in the CD14 gene is associated with Kawasaki disease (KD). STUDY DESIGN: We extracted DNA from the whole blood of 69 control children and 67 patients with KD. We determined a polymorphism in the CD14 gene at position -159 upstream from the major transcription site (CD14/-159) by restriction fragment assay. We then investigated the association between CD14/-159 and the onset of KD and development of coronary artery lesion (CAL). RESULTS: The genomic and allelic frequencies of the polymorphism were not different between normal children and KD patients. The KD patients with TT genotypes at CD14/-159 had more CAL complications than those with CT and CC (OR, 4.05; 95% CI, 1.34-12.22). The frequencies of the T allele was significantly higher than that of the C allele in KD patients with CAL (OR, 2.20; 95% CI, 1.23-3.94). Their data were confirmed in the patients whether the patients were treated with intravenous gamma-globulin. KD patients with TT genotypes had significantly higher levels of C-reactive protein and vascular endothelial growth factor, which had previously been reported as risk factors for CAL, than those with CC genotypes. CONCLUSION: These results indicate that the T allele and TT genotype at CD14/-159 are risk factors for CAL in KD, and that the development of CAL in KD may be related to the magnitude of CD14 toll-like receptor response.

Engraftment and dissemination of T lymphocytes from primary haemophagocytic lymphohistiocytosis in scid mice.

Although primary haemophagocytic lymphohistiocytosis (HLH) is a genetic disorder of T lymphocytes, it remains unclear why T lymphocytes of primary HLH patients preferentially infiltrate the central nervous system and peripheral blood, in addition to the reticuloendothelial systems. We engrafted Herpesvirus saimiri (HVS)-immortalized T-lymphocyte lines established from primary HLH patients into severe combined immunodeficient (scid) mice and examined their capacity to infiltrate mouse organs. A diffuse infiltration of human T lymphocytes was detected in each organ of scid mice treated with 1 x 10(6) T lymphocytes from all four primary HLH patients assessed, whereas no infiltration of T lymphocytes from healthy individuals was observed in any organ. The infiltration of T lymphocytes was mainly observed in the lung, brain and peripheral blood, in association with haemophagocytosis. These cells were positive for HLA-DR, CD3 and either CD8 or CD4, but negative for CD68. Certain markers of proliferation and apoptotic activities were highly positive in these cells. There was no difference between the infiltration pattern of T lymphocytes of primary HLH patients with a perforin deficiency and those without. By Southern blot analysis, T lymphocytes infiltrating mouse organs were observed to be polyclonal. These findings suggest that our murine model implementing HVS-immortalized human T lymphocytes is suitable to clarify the pathogenesis of primary HLH.